Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity

Breast Cancer Res. 2018 Aug 7;20(1):87. doi: 10.1186/s13058-018-1011-1.

Abstract

Background: Breast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome. Up to 80% of individuals with a Li-Fraumeni-like phenotype do not harbor detectable causative germline TP53 variants. Yet, no systematic panel analyses for a wide range of cancer predisposition genes have been conducted on cohorts of women with breast cancer fulfilling Li-Fraumeni(-like) clinical diagnostic criteria.

Methods: To specifically help explain the diagnostic gap of TP53 wild-type Li-Fraumeni(-like) breast cancer cases, we performed array-based CGH (comparative genomic hybridization) and panel-based sequencing of 94 cancer predisposition genes on 83 breast cancer patients suggestive of Li-Fraumeni syndrome who had previously had negative test results for causative BRCA1, BRCA2, and TP53 germline variants.

Results: We identified 13 pathogenic or likely pathogenic germline variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels. Three patients presented as double-mutation carriers involving two different genes each. In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in established hereditary breast cancer susceptibility genes (i.e., PALB2, CHEK2, ATM). Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibility to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A/p14ARF, and RUNX1).

Conclusions: Our study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoallelic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-like) syndrome lacking TP53 variants in coding regions.

Keywords: Breast cancer; CDKN2A; FANCA; Fanconi pathway; HBOC; Li-Fraumeni syndrome; Li-Fraumeni-like syndrome; RECQ family; TP53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Breast Neoplasms / genetics*
  • Cohort Studies
  • DNA Copy Number Variations
  • DNA Mutational Analysis / methods
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing / methods
  • Germ-Line Mutation / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Li-Fraumeni Syndrome / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide
  • Tumor Suppressor Protein p53 / genetics
  • Young Adult

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53

Supplementary concepts

  • Breast Cancer, Familial